U.S. patent application number 10/598262 was filed with the patent office on 2007-07-05 for histamine h3 receptor antagonists, preparation and therapeutic uses.
Invention is credited to Lisa Selsam Beavers, Robert Alan Gadski, Philip Arthur Hipskind, Cynthia Darshini Jesudason, Craig William Lindsley, Karen Lynn Lobb, Richard Todd Pickard.
Application Number | 20070155754 10/598262 |
Document ID | / |
Family ID | 34910936 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070155754 |
Kind Code |
A1 |
Beavers; Lisa Selsam ; et
al. |
July 5, 2007 |
Histamine h3 receptor antagonists, preparation and therapeutic
uses
Abstract
The present invention discloses novel compounds of Formula I or
pharmaceutically acceptable salts thereof which have histamine-H3
receptor antagonist activity as well as methods for preparing such
compounds. In another embodiment, the invention discloses
pharmaceutical compositions comprising compounds of Formula I as
well as methods of using them to treat obesity and other histamine
H3 receptor-related diseases. ##STR1##
Inventors: |
Beavers; Lisa Selsam;
(Franklin, IN) ; Gadski; Robert Alan;
(Indianapolis, IN) ; Hipskind; Philip Arthur; (New
Palestine, IN) ; Jesudason; Cynthia Darshini;
(Indianapolis, IN) ; Lobb; Karen Lynn;
(Indianapolis, IN) ; Pickard; Richard Todd;
(Noblesville, IN) ; Lindsley; Craig William;
(Schwenksville, PA) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION
P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
34910936 |
Appl. No.: |
10/598262 |
Filed: |
February 22, 2005 |
PCT Filed: |
February 22, 2005 |
PCT NO: |
PCT/US05/05491 |
371 Date: |
August 23, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60547758 |
Feb 25, 2004 |
|
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|
Current U.S.
Class: |
514/254.01 ;
514/326; 514/422; 544/372; 546/209; 548/518 |
Current CPC
Class: |
C07D 295/125 20130101;
C07D 295/192 20130101; C07D 207/09 20130101; C07D 295/155 20130101;
C07D 295/096 20130101; C07D 487/04 20130101; C07D 295/02
20130101 |
Class at
Publication: |
514/254.01 ;
514/326; 514/422; 544/372; 546/209; 548/518 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/454 20060101 A61K031/454; A61K 31/4025
20060101 A61K031/4025; C07D 403/14 20060101 C07D403/14 |
Claims
1. A compound structurally represented by Formula I ##STR49## or
pharmaceutically acceptable salts thereof wherein: R.sup.1 is
##STR50## R.sup.2 is ##STR51## wherein; R.sup.3 is hydrogen,
--(C.sub.1-C.sub.4) alkyl, R.sup.4 is --(C.sub.1-C.sub.4) alkyl,
--(C.sub.1-C.sub.4) alkylene-phenyl, wherein R.sup.3 and R.sup.4
can cyclize to form, together with the nitrogen to which they are
attached, a five or six-membered ring, wherein optionally one of
the carbons of the ring formed by said nitrogen, R.sup.3, and
R.sup.4, is replaced by a nitrogen or oxygen, and wherein said ring
is optionally further substituted by R.sup.5, and R.sup.5 is
hydrogen, --(C.sub.1-C.sub.4) alkyl, wherein optionally R.sup.5
forms a 3 to five membered ring with the nitrogen containing ring
to which it is attached, --(C.sub.1-C.sub.4) alkylene
--N-pyrrolidinyl, --(C.sub.1-C.sub.4) alkylene --N-piperidinyl;
provided that when R.sup.1 is --CH.sub.2NR.sup.3R.sup.4 or
--CONR.sup.3R.sup.4 then R.sup.2 is ##STR52##
2. A compound structurally represented by Formula II, ##STR53## or
pharmaceutically acceptable salts thereof wherein: Z is -carbonyl-,
or --CH.sub.2--, R.sup.2 is ##STR54## wherein; R.sup.3 is hydrogen,
--(C.sub.1-C.sub.4) alkyl, R.sup.4 is --(C.sub.1-C.sub.4)
alkylene-phenyl, wherein R.sup.3 and R.sup.4 can cyclize to form,
together with the nitrogen to which they are attached, a five or
six-membered ring, wherein optionally one of the carbons of the
ring formed by said nitrogen, R.sup.3, and R.sup.4, is replaced by
a nitrogen or oxygen, and wherein said ring is optionally further
substituted by R.sup.5, and R.sup.5 is hydrogen,
--(C.sub.1-C.sub.4) alkyl, wherein optionally R.sup.5 forms a 3 to
five membered ring with the nitrogen containing ring to which it is
attached, --(C.sub.1-C.sub.4) alkylene --N-pyrrolidinyl,
--(C.sub.1-C.sub.4) alkylene --N-- piperidinyl.
3. The compound of claim 1, wherein R.sup.1 is CONR.sup.3R.sup.4,
and R.sup.3 and R.sup.4 cyclize to form, together with the nitrogen
to which they are attached, a five membered ring, and said ring is
further substituted by --CH.sub.2-- pyrrolidinyl.
4. The compound of claim 1, wherein R.sup.1 is
CH.sub.2NR.sup.3R.sup.4, and R.sup.3 and R.sup.4 cyclize to form,
together with the nitrogen to which they are attached, a five
membered ring, and said ring is further substituted by --CH.sub.2--
pyrrolidinyl.
5. The compound of claim 3 wherein R.sup.2 is NR.sup.3R.sup.4, and
R.sup.3 and R.sup.4 cyclize to form, together with the nitrogen to
which they are attached, a five membered ring.
6. The compound of claim 4 wherein R.sup.2 is NR.sup.3R.sup.4, and
R.sup.3 and R.sup.4 cyclize to form, together with the nitrogen to
which they are attached, a five membered ring.
7. The compound of claim 1, further represented by any one of the
formula selected from the group consisting of: TABLE-US-00004 Exam-
ple Number 1 ##STR55## 2 ##STR56## 3 ##STR57## 4 ##STR58## 5
##STR59## 6 ##STR60## 8 ##STR61## 9 ##STR62## 13 ##STR63## 14
##STR64## 15 ##STR65## 16 ##STR66## 17 ##STR67## 18 ##STR68##
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition which comprises a compound of claim
1 and a pharmaceutically acceptable carrier.
9. A method for treatment or prevention of a cognitive disorder
which comprises administering to a subject in need of such
treatment or prevention an effective amount of a compound of claim
1.
10. The method of claim 9 wherein the antagonist is a
pharmaceutical composition of claim 8.
11. A method for treatment or prevention of obesity which comprises
administering to a subject in need of such treatment or prevention
an effective amount of a compound of claim 1.
12. The method of claim 11 wherein the antagonist is a
pharmaceutical composition of claim 8.
13. A method for treatment or prevention of a wakefulness disorder
which comprises administering to a subject in need of such
treatment or prevention an effective amount of a compound of claim
1.
14. The method of claim 13 wherein the antagonist is a
pharmaceutical composition of claim 8.
15. (canceled)
16. A compound selected from the group consisting of:
TABLE-US-00005 Example Number 7 ##STR69## 10 ##STR70## 11 ##STR71##
12 ##STR72##
or a pharmaceutically acceptable salt thereof.
Description
[0001] The present invention relates to histamine H3 receptor
antagonists, and as such are useful in the treatment of disorders
responsive to the inactivation of histamine H3 receptors, such as
obesity, cognitive disorders, attention deficit disorders, and the
like.
[0002] The histamine H3 receptor (H3R) is a presynaptic
autoreceptor and hetero-receptor found in the peripheral and
central nervous system and regulates the release of histamine and
other neurotransmitters, such as serotonin and acetylcholine. This
is an example of an H3 receptor mediated cellular response. Recent
evidence suggests that the H3 receptor shows intrinsic,
constitutive activity, in vitro as well as in vivo (i.e. it is
active in the absence of an agonist). Compounds acting as inverse
agonists can inhibit this activity. A histamine H3 receptor
antagonist or inverse agonist would therefore be expected to
increase the release of H3 receptor-regulated neurotransmitters in
the brain. A histamine H3 receptor agonist, on the contrary, leads
to an inhibition of the biosynthesis of histamine and an inhibition
of the release of histamine and also of other neurotransmitters
such as serotonin and acetylcholine. The histamine H3 receptor is
relatively neuron specific and inhibits the release of a number of
monamines, including histamine. Selective antagonism of the
histamine H3 receptor raises brain histamine levels and inhibits
such activities as food consumption while minimizing non-specific
peripheral consequences. Antagonists of the histamine H3 receptor
increase synthesis and release of cerebral histamine and other
monoamines. By this mechanism, they induce a prolonged wakefulness,
improved cognitive function, reduction in food intake and
normalization of vestibular reflexes. Accordingly, the histamine H3
receptor is an important target for new therapeutics in Alzheimer
disease, mood and attention adjustments, cognitive deficiencies,
obesity, dizziness, schizophrenia, epilepsy, sleeping disorders,
narcolepsy and motion sickness.
[0003] The majority of histamine H3 receptor antagonists to date
resemble histamine in possessing an imidazole ring generally
substituted in the 4(5) position (Ganellin et al., Ars
Pharmaceutica, 1995, 36:3, 455-468). A variety of patents and
patent applications directed to antagonists and agonists having
such structures include EP 197840, EP 494010, WO 97/29092, WO
96/38141, and WO 96/38142. These imidazole-containing compounds
have the disadvantage of poor blood-brain barrier penetration,
interaction with cytochrome P-450 proteins, and hepatic and ocular
toxicities.
[0004] Non-imidazole neuroactive compounds such as beta histamines
(Arrang, Eur. J. Pharm. 1985, 111:72-84) demonstrated some
histamine H3 receptor activity but with poor potency. EP 978512
published Mar. 1, 2000 discloses non-imidazole aryloxy alkylamines
histamine H3 receptor antagonists but does not disclose the
affinity, if any, of these antagonists for recently identified
histamine receptor GPRv53, described below. EP 0982300A2 (pub. Mar.
1, 2000) discloses non-imidazole alkyamines as histamine HS
receptor ligands. The subject invention is distinct from EP
0982300A2 in the structure and activities of the present
compounds.
[0005] Histamine mediates its activity via four receptor subtypes,
H1R, H2R, H3R and a newly identified receptor designated GPRv53
[(Oda T., et al., J. Biol. Chem. 275 (47): 36781-6 (2000)].
Although relatively selective ligands have been developed for H1R,
H2R and H3R, few specific ligands have been developed that can
distinguish H3R from GPRv53. GPRv53 is a widely distributed
receptor found at high levels in human leukocytes. Activation or
inhibition of this receptor could result in undesirable side
effects when targeting antagonism of the H3R receptor. Furthermore,
the identification of this new receptor has fundamentally changed
histamine biology and must be considered in the development of
histamine H3 receptor antagonists.
[0006] Because of the unresolved deficiencies of the compounds
described above, there is a continuing need for improved methods
and compositions to treat disorders associated with histamine H3
receptors.
[0007] The present invention provides compounds that are useful as
histamine H3 receptor antagonists. In another aspect, the present
invention provides compounds that are useful as selective
antagonists of the histamine H3 receptor but have little or no
binding affinity of GPRv53. In another aspect the present invention
includes methods of making the compounds of Formula I or II or III.
In yet another aspect, the present invention provides
pharmaceutical compositions comprising antagonists of the histamine
H3 receptor.
[0008] In yet another aspect, the present invention provides
compounds, pharmaceutical compositions, and methods useful in the
treatment of obesity, cognitive disorders, attention deficit
disorders and other disorders associated with histamine H3
receptor.
[0009] The present invention is a compound structurally represented
by Formula I; ##STR2## or pharmaceutically acceptable salts thereof
wherein: R.sup.1 is ##STR3## R.sup.2 is ##STR4## wherein; [0010]
R.sup.3 is hydrogen, [0011] --(C.sub.1-C.sub.4) alkyl, [0012]
R.sup.4 is [0013] --(C.sub.1-C.sub.4) alkyl, [0014]
--(C.sub.1-C.sub.4) alkylene-phenyl, [0015] wherein R.sup.3 and
R.sup.4 can cyclize to form, together with the nitrogen to which
they are attached, a five or six-membered ring, wherein optionally
one of the carbons of the ring formed by said nitrogen, R.sup.3,
and R.sup.4, is replaced by a nitrogen or oxygen, and wherein said
ring is optionally further substituted by R.sup.5, and R.sup.5 is
hydrogen, [0016] --(C.sub.1-C.sub.4) alkyl, wherein optionally
R.sup.5 forms a three to five membered ring with the nitrogen
containing ring to which it is attached, [0017] --(C.sub.1-C.sub.4)
alkylene --N-pyrrolidinyl, [0018] --(C.sub.1-C.sub.4) alkylene
--N-- piperidinyl.
[0019] While all of the compounds of the present invention are
useful, certain of the compounds are particularly interesting and
are preferred. The following listing sets out several groups of
preferred compounds. It will be understood that each of the
listings may be combined with other listings to create additional
groups of preferred embodiments. [0020] 1. The compound of Formula
I, wherein R.sup.1 is CONR.sup.3R.sup.4, and R.sup.3 and R.sup.4
cyclize to form, together with the nitrogen to which they are
attached, a five membered ring, and said ring is further
substituted by --CH.sub.2-- pyrrolidinyl. [0021] 2. The compound of
Formula I, wherein R.sup.1 is CH.sub.2NR.sup.3R.sup.4, and R.sup.3
and R.sup.4 cyclize to form, together with the nitrogen to which
they are attached, a five membered ring, and said ring is further
substituted by --CH.sub.2-- pyrrolidinyl. [0022] 3. The compound of
Formula I wherein R.sup.2 is NR.sup.3R.sup.4, and R.sup.3 and
R.sup.4 cyclize to form, together with the nitrogen to which they
are attached, a five membered ring. [0023] 4. The compound of
Formula I wherein R.sup.2 is NR.sup.3R.sup.4, and R.sup.3 and
R.sup.4 cyclize to form, together with the nitrogen to which they
are attached, a five membered ring. [0024] 5. A compound of Formula
II ##STR5## [0025] wherein Z is -carbonyl-, or --CH.sub.2--. [0026]
6. A compound of Formula III ##STR6##
[0027] The present invention is a pharmaceutical composition which
comprises a compound of Formula I or II or III and a
pharmaceutically acceptable carrier. Pharmaceutical formulations of
Formula I or II or III can provide a method of selectively
increasing histamine levels in cells by contacting the cells with
an antagonist of the histamine H3 receptor, the antagonists being a
compound of Formula I or II or III. Thus, the methods of this
invention encompass a prophylactic and therapeutic administration
of a compound of Formula I or II or III.
[0028] The present invention further provides an antagonist of
Formula I or II or III which is characterized by having little or
no binding affinity for the histamine receptor GPRv53. Thus, a
pharmaceutical preparation of Formula I or II or III can be useful
in the treatment or prevention of obesity, cognitive disorders,
attention deficit disorders and the like, which comprises
administering to a subject in need of such treatment or prevention
an effective amount of a compound of Formula I or II or III. In
addition, a pharmaceutical preparation of Formula I or II or III
can be useful in the treatment or prevention of a disorder or
disease in which inhibition of the histamine H3 receptor has a
beneficial effect or the treatment or prevention of eating
disorders which comprises administering to a subject in need of
such treatment or prevention an effective amount of a compound of
Formula I or II or III.
DETAILED DESCRIPTION OF THE INVENTION
[0029] General terms used in the description of compounds,
compositions, and methods herein described, bear their usual
meanings. Throughout the instant application, the following terms
have the indicated meanings:
[0030] The term "GPRv53" means a recently identified novel
histamine receptor as described in Oda, et al., supra. Alternative
names for this receptor are PORT3 or H4R.
[0031] The term "H3R" means to the histamine H3 receptor that
inhibits the release of a number of monoamines, including
histamine.
[0032] The term "H1R" means to the histamine H1 receptor
subtype.
[0033] The term "H2R" means to the histamine H2 receptor
subtype.
[0034] The term "selective H3R antagonists" is defined as the
ability of a compound of the present invention to block
forskolin-stimulated cAMP production in response to agonist R
(-).alpha. methylhistamine.
[0035] In the general formulae of the present document, the general
chemical terms have their usual meanings. For example;
[0036] "Alkylene" are a saturated hydrocarbyldiyl radical of
straight or branched configuration made up of from 1 to 4 carbon
atoms. Included within the scope of this term are methylene,
1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane diyl, 1,2-propane
diyl, 1,3 butane-diyl, 1,4-butane diyl, and the like.
[0037] "C.sub.3-C.sub.7 cycloalkylene" are a saturated
hydrocarbyldiyl radical of cyclic configuration, optionally
branched, made up of from 3 to 7 carbon atoms. Included within the
scope of this term are cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl, and the like.
[0038] "Alkyl" are one to six carbon atoms such as methyl, ethyl,
propyl, butyl, pentyl, hexyl, and the like, and isomeric forms
thereof.
[0039] "Aryl" are six to twelve carbon atoms such as phenyl,
alpha-naphthyl, beta-naphthyl, m-methylphenyl,
p-trifluoromethylphenyl and the like. The aryl groups can also be
substituted with one to 3 hydroxy, fluoro, chloro, or bromo
groups.
[0040] "Cycloalkyl" are three to six carbon atoms such as
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the
like.
[0041] "--(C.sub.1-C.sub.4) alkylene-N-pyrrolidinyl" is; ##STR7##
[0042] wherein n=1-4
[0043] "--(C.sub.1-C.sub.4) alkylene-N-piperidinyl" is; ##STR8##
[0044] wherein n=1-4
[0045] "Halogen" or "halo" means fluoro, chloro, bromo and
iodo.
[0046] "Composition" means a pharmaceutical composition and is
intended to encompass a pharmaceutical product comprising the
active ingredient(s), Formula I or II or III, and the inert
ingredient(s) that make up the carrier. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier.
[0047] The term "unit dosage form" means physically discrete units
suitable as unitary dosages for human subjects and other non-human
animals, each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical carrier.
[0048] The terms "treating" and "treat," as used herein, include
their generally accepted meanings, i.e., preventing, prohibiting,
restraining, alleviating, ameliorating, slowing, stopping, or
reversing the progression or severity of a pathological condition,
described herein.
[0049] The invention includes tautomers, enantiomers and other
stereoisomers of the compounds also. Thus, as one skilled in the
art knows, certain aryls may exist in tautomeric forms. Such
variations are contemplated to be within the scope of the
invention. It will be understood that, as used herein, references
to the compounds of Formula I or II or III are meant to also
include the pharmaceutical salts, its enantiomers and racemic
mixtures thereof.
[0050] As used herein, the term "stereoisomer" refers to a compound
made up of the same atoms bonded by the same bonds but having
different three-dimensional structures which are not
interchangeable. The three-dimensional structures are called
configurations. As used herein, the term "enantiomer" refers to two
stereoisomers whose molecules are nonsuperimposable mirror images
of one another. The term "chiral center" refers to a carbon atom to
which four different groups are attached. As used herein, the term
"diastereomers" refers to stereoisomers which are not enantiomers.
In addition, two diastereomers which have a different configuration
at only one chiral center are referred to herein as "epimers." The
terms "racemate," "racemic mixture" or "racemic modification" refer
to a mixture of equal parts of enantiomers.
[0051] The term "enantiomeric enrichment" as used herein refers to
the increase in the amount of one enantiomer as compared to the
other. A convenient method of expressing the enantiomeric
enrichment achieved is the concept of enantiomeric excess, or "ee,"
which is found using the following equation: ee = E 1 - E 2 E 1 + E
2 .times. 100 ##EQU1## wherein E.sup.1 is the amount of the first
enantiomer and E.sup.2 is the amount of the second enantiomer.
Thus, if the initial ratio of the two enantiomers is 50:50, such as
is present in a racemic mixture, and an enantiomeric enrichment
sufficient to produce a final ratio of 70:30 is achieved, the ee
with respect to the first enantiomer is 40%. However, if the final
ratio is 90:10, the ee with respect to the first enantiomer is 80%.
An ee of greater than 90% is preferred, an ee of greater than 95%
is most preferred and an ee of greater than 99% is most especially
preferred. Enantiomeric enrichment is readily determined by one of
ordinary skill in the art using standard techniques and procedures,
such as gas or high performance liquid chromatography with a chiral
column. Choice of the appropriate chiral column, eluent and
conditions necessary to effect separation of the enantiomeric pair
is well within the knowledge of one of ordinary skill in the art.
In addition, the specific stereoisomers and enantiomers of
compounds of Formula I or II or III can be prepared by one of
ordinary skill in the art utilizing well known techniques and
processes, such as those disclosed by J. Jacques, et al.,
"Enantiomers, Racemates, and Resolutions," John Wiley and Sons,
Inc., 1981, and E. L. Eliel and S. H. Wilen, "Stereochemistry of
Organic Compounds," (Wiley-Interscience 1994), and European Patent
Application No. EP-A-838448, published Apr. 29, 1998. Examples of
resolutions include recrystallization techniques or chiral
chromatography.
[0052] Some of the compounds of the present invention have one or
more chiral centers and may exist in a variety of stereoisomeric
configurations. As a consequence of these chiral centers, the
compounds of the present invention occur as racemates, mixtures of
enantiomers and as individual enantiomers, as well as diastereomers
and mixtures of diastereomers. All such racemates, enantiomers, and
diastereomers are within the scope of the present invention.
[0053] The terms "R" and "S" are used herein as commonly used in
organic chemistry to denote specific configuration of a chiral
center. The term "R" (rectus) refers to that configuration of a
chiral center with a clockwise relationship of group priorities
(highest to second lowest) when viewed along the bond toward the
lowest priority group. The term "S" (sinister) refers to that
configuration of a chiral center with a counterclockwise
relationship of group priorities (highest to second lowest) when
viewed along the bond toward the lowest priority group. The
priority of groups is based upon their atomic number (in order of
decreasing atomic number). A partial list of priorities and a
discussion of stereochemistry is contained in "Nomenclature of
Organic Compounds: Principles and Practice," (J. H. Fletcher, et
al., eds., 1974) at pages 103-120.
[0054] The designation refers to a bond that protrudes forward out
of the plane of the page. The designation refers to a bond that
protrudes backward out of the plane of the page. The designation
refers to a bond wherein the stereochemistry is not defined.
[0055] In general, the term "pharmaceutical" when used as an
adjective means substantially non-toxic to living organisms. For
example, the term "pharmaceutical salt" as used herein, refers to
salts of the compounds of Formula I or II or III which are
substantially non-toxic to living organisms. See, e.g., Berge, S.
M, Bighley, L. D., and Monkhouse, D. C., "Pharmaceutical Salts," J.
Pharm. Sci., 66:1, 1977. Typical pharmaceutical salts include those
salts prepared by reaction of the compounds of Formula I or II or
III with an inorganic or organic acid or base. Such salts are known
as acid addition or base addition salts respectively. These
pharmaceutical salts frequently have enhanced solubility
characteristics compared to the compound from which they are
derived, and thus are often more amenable to formulation as liquids
or emulsions.
[0056] The term "acid addition salt" refers to a salt of a compound
of Formula I or II or III prepared by reaction of a compound of
Formula I or II or III with a mineral or organic acid. For
exemplification of pharmaceutical acid addition salts see, e.g.,
Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci.,
66:1, 1977. Since compounds of this invention can be basic in
nature, they accordingly react with any of a number of inorganic
and organic acids to form pharmaceutical acid addition salts.
[0057] The pharmaceutical acid addition salts of the invention are
typically formed by reacting the compound of Formula I or II or III
with an equimolar or excess amount of acid. The reactants are
generally combined in a mutual solvent such as diethylether,
tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the
like. The salts normally precipitate out of solution within about
one hour to about ten days and can be isolated by filtration or
other conventional methods.
[0058] Acids commonly employed to form acid addition salts are
inorganic acids such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and
acids commonly employed to form such salts are inorganic acids such
as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, phosphoric acid, and the like, and organic acids, such as
p-toluenesulfonic acid, methanesulfonic acid, oxalic acid,
p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric
acid, benzoic acid, acetic acid and the like. Examples of such
pharmaceutically acceptable salts thus are the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, isobutyrate, caproate,
heptanoate, propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,
xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,
citrate, lactate, .beta.-hydroxybutyrate, glycollate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, mandelate and the like.
[0059] The term "base addition salt" refers to a salt of a compound
of Formula I or II or III prepared by reaction of a compound of
Formula I or II or III with a mineral or organic base. For
exemplification of pharmaceutical base addition salts see, e.g.,
Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci.,
66:1, 1977. This invention also contemplates pharmaceutical base
addition salts of compounds of Formula I or II or III. The skilled
artisan would appreciate that some compounds of Formula I or II or
III may be acidic in nature and accordingly react with any of a
number of inorganic and organic bases to form pharmaceutical base
addition salts. Examples of pharmaceutical base addition salts are
the ammonium, lithium, potassium, sodium, calcium, magnesium,
methylamine, diethyl amino, ethylene diamino, cyclohexylamino, and
ethanolamino salts, and the like of a compound of Formula I or II
or III.
[0060] The compounds of Formula I or II or III, when existing as a
diastereomeric mixture, may be separated into diastereomeric pairs
of enantiomers by, for example, fractional crystallization from a
suitable solvent, for example methanol or ethyl acetate or a
mixture thereof. The pair of enantiomers thus obtained may be
separated into individual stereoisomers by conventional means, for
example by the use of an optically active acid as a resolving
agent. Alternatively, any enantiomer of a compound of the formula
may be obtained by stereospecific synthesis using optically pure
starting materials or reagents of known configuration or through
enantioselective synthesis.
[0061] The compounds of Formula I or II or III can be prepared by
one of ordinary skill in the art following a variety of procedures,
some of which are illustrated in the procedures and schemes set
forth below. The particular order of steps required to produce the
compounds of Formula I or II or III is dependent upon the
particular compound to being synthesized, the starting compound,
and the relative liability of the substituted moieties. The
reagents or starting materials are readily available to one of
skill in the art, and to the extent not commercially available, are
readily synthesized by one of ordinary skill in the art following
standard procedures commonly employed in the art, along with the
various procedures and schemes set forth below.
[0062] The following Preparations and Examples are provided to
better elucidate the practice of the present invention and should
not be interpreted in any way as to limit the scope of the same.
Those skilled in the art will recognize that various modifications
may be made while not departing from the spirit and scope of the
invention. All publications mentioned in the specification are
indicative of the level of those skilled in the art to which this
invention pertains.
[0063] The terms and abbreviations used in the instant Preparations
and Examples have their normal meanings unless otherwise
designated. For example, as used herein, the following terms have
the meanings indicated: "eq" refers to equivalents; "N" refers to
normal or normality, "M" refers to molar or molarity, "g" refers to
gram or grams, "mg" refers to milligrams; "L" refers to liters;
"mL" refers to milliliters; ".mu.L" refers to microliters; "mol"
refers to moles; "mmol" refers to millimoles; "psi" refers to
pounds per square inch; "min" refers to minutes; "h" or "hr" refers
to hours; ".degree.C." refers to degrees Celsius; "TLC" refers to
thin layer chromatography; "HPLC" refers to high performance liquid
chromatography; "R.sub.f" refers to retention factor; "R.sub.t"
refers to retention time; ".delta." refers to part per million
down-field from tetramethylsilane; "MS" refers to mass
spectrometry, Observed Mass indicates (M+1) unless indicated
otherwise. "MS(FD)" refers to field desorption mass spectrometry,
"MS(IS)" refers to ion spray mass spectrometry, "MS(FIA)" refers to
flow injection analysis mass spectrometry, "MS(FAB)" refers to fast
atom bombardment mass spectrometry, "MS(EI)" refers to electron
impact mass spectrometry, "MS(ES)" refers to electron spray mass
spectrometry, "MS(APCI)" refers to atmospheric pressure chemical
ionization mass spectrometry. "UV" refers to ultraviolet
spectrometry, ".sup.1H NMR" refers to proton nuclear magnetic
resonance spectrometry. In addition, "IR" refers to infra red
spectrometry, and the absorption maxima listed for the IR spectra
are only those of interest and not all of the maxima observed. "RT"
refers to room temperature. ##STR9##
Preparation 1
(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-cyclopentyl-amine
[0064] Charged 50 mL round bottomed flask with 6-bromo-2-tetralone
(0.750 g., 3.33 mmoles., 1.0 eq.), cylcopentylamine (0.567 g.,
0.648 mL., 6.66 mmoles., 2.0 eq.) and catalytic amount of tosic
acid. Fitted flask with a Dean-Stark trap and heated reaction
mixture overnight at 155.degree. C. The next day, removed remaining
solvent from reaction mixture using reduced pressure. Added 25 mL
of methanol and placed reaction mixture on an ice bath. Added
sodium borohydride (0.630 g, 16.6 mmoles, 5.0 eq.). Removed ice
bath and allowed to stir for several hours. Partitioned reaction
mixture between ethyl acetate and 1.0 N HCl aqueous solution.
Extracted organic layer two times more with 1.0 N HCl solution.
Combined acidic extractions and basified with 5.0 N NaOH. Extracted
basic aqueous with methylene chloride three times. Combined organic
extracts and dried over Na.sub.2SO.sub.4. Removed solvents using
reduced pressure to obtain 0.429 g. (crude yield=43%). Purified
using a reverse phase column and acetonitrile:TFA buffer solvent
gradient. Collected TFA salt of
6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-cyclopentyl-amine.
Partitioned the product between methylene chloride and 2.0N sodium
carbonate solution. Washed organic layer with 2.0N sodium carbonate
a second time and then with brine. Dried organic layer over sodium
sulfate and removed solvent via reduced pressure to obtain 0.324 g.
(yield=33%). Mass spectrum (APCI): 294 (M.sup.++1). ##STR10##
EXAMPLE 1
Synthesis of (6-Cyclopentyl
amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidin-1-ylmethyl-pyrrol-
idin-1-yl)-methanone
[0065] Procedure A: Charged 10 mL round bottomed flask with
6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-cyclopentyl-amine
(0.200 g, 0.678 mmoles, 1.0 eq.);
(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidinone (0.152 g., 0.986
mmoles., 1.45 eq.); tri-n-butylamine (0.138 g., 0.748 mmoles., 1.10
eq.); 1 mL DMF; and trans-dibromobis(triphenylphosphine)palladium
(II) (8.1 mg., 0.010 mmoles., 0.015 eq.). Flushed reaction flask
with carbon monoxide. Heated reaction mixture under a carbon
monoxide balloon at 85.degree. C. overnight. The next day,
partitioned the reaction mixture between ethyl ether and water.
Extracted water layer two times more with ethyl ether. Washed the
combined organic extracts with brine. Dried organic extracts over
sodium sulfate and removed solvents under reduced pressure to
obtain 150.1 mg. (crude yield=56%) Submitted for reverse phase
chromatography using Waters Xterra MS C18 5 uM 19.times.100 mm
column and acetonitrile and 5 mM aqueous sodium carbonate buffer
solvent system. Obtained 44.1 mg. (yield=16%). Mass spectrum
(APCI): 396 (M.sup.++1). ##STR11##
EXAMPLE 2
[0066]
(6-Piperidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidi-
n-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from
1-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidine and
(S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner
substantially analogous to Procedure A. (See herein Example 1).
Starting material,
(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidine, was
prepared from 6-bromo-2-tetralone and piperidine in a manner
substantially analogous to Preparation 1. Mass Spectrum (ES+) 396.
##STR12##
EXAMPLE 3
[0067]
(2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(6-pyrrolidin-1-yl-5,6,7-
,8-tetrahydro-naphthalen-2-yl)-methanone is prepared from
1-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pyrrolidine and
(S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner
substantially analogous to Procedure A. (See herein Example 1).
Starting material,
(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pyrrolidine, was
prepared from 6-bromo-2-tetralone and pyrrolidine in a manner
substantially analogous to Preparation 1. Mass Spectrum (APCI)
382(M.sup.++1). ##STR13##
EXAMPLE 4
[0068]
(6-Benzylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidin-1-
-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from
benzyl-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine and
(S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner
substantially analogous to Procedure A. (See herein Example 1).
Starting material,
benzyl-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine, can be
prepared from 6-bromo-2-tetralone and benzylamine in a manner
substantially analogous to Preparation 1. Mass spectrum (APCI)
418(M.sup.++1). ##STR14##
EXAMPLE 5
[0069]
(6-Butylamino-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidin-1--
ylmethyl-pyrrolidin-1-yl)-methanone is prepared from
(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-butyl-amine and
(S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner
substantially analogous to Procedure A. (See herein Example 1).
Starting material,
(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-butyl-amine, was
prepared from 6-bromo-2-tetralone and n-butylamine in a manner
substantially analogous to Preparation 1. Mass spectrum (APCI)
384(M.sup.++1). ##STR15##
EXAMPLE 6
[0070]
(6-Morpholin-4-yl-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidi-
n-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from
4-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-morpholine and
(S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner
substantially analogous to Procedure A. (See herein Example 1).
Starting material,
4-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-morpholine, was
prepared from 6-bromo-2-tetralone and morpholine in a manner
substantially analogous to Preparation 1. Mass spectrum (APCI):
389(M.sup.++1). ##STR16##
EXAMPLE 7
[0071]
6-Pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid
benzylamide; compound with trifluoro-acetic acid is prepared from
1-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pyrrolidine and
benzylamine in a manner substantially analogous to Procedure A
except reverse phase purification used TFA buffer instead of sodium
carbonate buffer. (See herein Example 1). Starting material,
1-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pyrrolidine, was
prepared from 6-bromo-2-tetralone and pyrrolidine in a manner
substantially analogous to Preparation 1. Mass spectrum (ES+) 335
(M.sup.++1). ##STR17##
Preparation 2
Synthesis of
6-Oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile
[0072] See also generally Org. Prep. Proced. Int. Vol. 32, No. 1,
2000, p. 88. Charged 50 mL round bottom flask with copper(I)
cyanide (1.34 g., 0.0150 moles, 1.12 eq.), 6-bromo-2-tetraline (3.0
g., 1.33 mmoles, 1.0 eq.) and 13 mL N-methylpyrrolidinone. Heated
for 5 hours at 180-200.degree. C. Allowed reaction mixture to stir
at room temperature over the weekend. Transferred reaction mixture
to 250 mL 3-necked, round bottomed flask fitted with a mechanical
stirrer, a condenser, and an addition funnel. Added 6.0 g.
Celite.RTM. and heated with stirring to 80.degree. C. Added 70 mL
water and 90 mL ethyl acetate to hot stirring reaction mixture.
Turned off heat and allowed to cool overnight with stirring. The
next day, filtered the reaction mixture through a Celite.RTM. pad.
Partitioned off water layer from filtered reaction mixture. Washed
ethyl acetate layer with water once, then washed with a 50:50
mixture of brine and water twice. Dripped organic layer through
sodium sulfate to dry and removed solvents under reduced pressure
to obtain 2.67 g. of light brown solid. Purified crude material via
Biotage FLASH 40 L.RTM. cartridge (175 g. of silica gel) using an
ethylacetate:hexane stepwise gradient. Obtained 1.77 g.
(yield=78%). Product was not completely pure, but used it as is in
the next reaction. H-NMR (CDCL3): 7.55 (1H,s), 7.53 (1H,d), 3.64
(2H, s), 3.12 (1H, t, J=7 Hz), 2.58 (1H, t, J=7 Hz. ##STR18##
Preparation 3
Synthesis of
6-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile
[0073] Added 100 mL toluene and 10 mL ethyl ether to
6-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile (1.77 g., 10.3
mmoles., 1.0 eq.) and N-methyl piperazine (1.24 g., 12.4 mmoles,
1.2 eq.). Added 4.3 g. 4A molecular sieves to the reaction mixture
and stirred at room temperature for 1.5 hours. Heated reaction
mixture to 55.degree. C. for 1 hour. NMR of reaction mixture sample
indicates starting material still present. Added another 0.8 eq. of
N-methyl piperazine (8.2 mmoles., 0.82 g., 0.91 mL) to the reaction
mixture and stirred at room temperature overnight. The next
morning, an NMR of a reaction mixture sample showed only a small
amount of starting material. Filtered off the molecular sieves with
filter paper and removed solvent under reduced pressure.
[0074] Added 60 mL. 10% acetic acid:methanol solution and sodium
cyanoborohydride (1.92 g., 30.5 moles, 3.0 eq.) to reaction
mixture. Allowed reaction mixture to stir at room temperature over
the weekend. Removed solvents under reduced pressure and
partitioned the reaction mixture between methylene chloride and 2.0
N sodium carbonate solution. Collected organic layer and extracted
aqueous two more time with methylene chloride. Combined organic
extracts and dripped through sodium sulfate to dry. Removed solvent
via reduced pressure to obtain 1.84 g. of brown oil.
[0075] Partitioned between 1.0N aqueous hydrochloric acid and 1:1
ethylacetate:ethylether. Collected acid layer and extracted organic
layer two more times with 1.0N aqueous hydrochloric solution.
Combined acid washes and extracted two times with ethylether.
Discarded the ethylether extracts. Basified the aqueous layer with
5.0 N aqueous sodium hydroxide solution. Extracted aqueous four
times with ethyl acetate. Dried combined ethylacetate extracts over
sodium sulfate and removed solvents via reduced pressure to obtain
0.95 g. of a brown oil. Passed this through a 10 g. Varian.RTM.
silica gel cartridge using 5% (2N ammonia in methanol):methylene
chloride solvent system as an eluant. Obtained 0.892 g of a brown
oil (yield=34%). Not completely pure, but used as is in next
reaction. Mass spectrum (APCI): 256 (M.sup.++1). ##STR19##
Preparation 4
Synthesis of
6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic
acid dihydrochloride
[0076] Charged 100 mL round bottomed flask with
6-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile
(0.791 g., 3.10 mmoles.), 9.0 mL water, and 11.0 mL concentrated
hydrochloric acid. Heated reaction mixture with a 100-110.degree.
C. oil bath overnight. Allowed to cool to room temperature and
filtered off the solid with a fretted funnel washing with water.
Dried the solid in a vacuum oven at 75.degree. C. overnight.
Obtained 0.4945 g. Took mother liquors and removed some of the
water via reduced pressure, stored in the refrigerator for several
weeks and collected a second crop of solid via vacuum filtration.
Washed second crop with water and dried in vacuum oven at
75.degree. C. overnight. Obtained another 0.2838 g. Combining the
two crops of desired product gave 0.7783 g. (yield=72%). Mass
spectrum (APCI): 275 (M.sup.++1) ##STR20##
EXAMPLE 8
Synthesis of
(4-Methyl-piperazin-1-yl)-[6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-
-naphthalen-2-yl]-methanone
[0077] Procedure B: Charged 4.0 mL glass vial with
6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic
acid dihydrochloride (75.0 mg, 0.216 mmoles, 1.3 eq.), 2.0 mL
methylene chloride, N-methyl piperazine (16.6 mg., 0.166 mmoles,
0.0184 mL, 1.00 eq.), and triethylamine (43.7 mg., 0.432 mmoles,
2.6 eq.). Added N-cyclohexyl carbodiimide N-methyl polystyrene HL
(Novabiochem, loading=1.92 mmoles/g, >0.172 g., >0.332
mmoles, >2.0 eq.) to the reaction mixture. Rotated reaction vial
at room temperature overnight. The next day, filtered off resin
washing alternately with methylene chloride and methanol. Purified
using a Biotage FLASH 25+M.RTM. cartridge (55 g. silica gel) and
eluting with a (2N NH3 in MeOH):CH.sub.2Cl.sub.2 stepwise gradient.
Obtained 51.5 mg. (yield=87%). Mass Spectrum (APCI): 357
(M.sup.++1). ##STR21##
EXAMPLE 9
Synthesis of
1-Methyl-4-[6-(2-pyrrolidin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-(2--
pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone
[0078] All operations performed under nitrogen. Charged 5 mL round
bottomed flask with
[6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-(2-pyrro-
lidin 1-ylmethyl-pyrrolidin-1-yl)-methanone (51.5 mg., 0.125
mmoles., 1.0 eq.) (See herein example 13) and 1.0 mL anhydrous THF.
Added 0.63 mL of 1.0 M lithium aluminum hydride in THF to the
reaction mixture. Refluxed the reaction for 5 hours. Allowed to
stir at room temperature for several days. Added. 0.25 mL water,
0.25 mL 5N sodium hydroxide, and 0.75 mL water. Filtered reaction
mixture through a pad of Celite.RTM. and removed solvents under
reduced pressure to obtain 82.7 mg. Purified crude material using a
Biotage FLASH 25+S.RTM. cartridge (27 g. of silica gel) and a step
wise (2N ammonia in methanol):methylene chloride solvent gradient.
Obtained 19.6 mg. (yield=39%). Mass spectrum (APCI): 397
(M.sup.++1). ##STR22##
EXAMPLE 10
[0079]
(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-[6-(4-methyl-piperazin-1-yl-
)-5,6,7,8-tetrahydro-naphthalen-2-yl]-methanone is prepared from
6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic
acid dihydrochloride and Octahydro-pyrrolo[1,2-a]pyrazine in a
manner substantially analogous to Procedure B (See herein Example
8). Observed mass 383 (M.sup.++1). ##STR23##
EXAMPLE 11
[0080]
6-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carbo-
xylic acid (2-pyrrolidin-1-yl-ethyl)-amide is prepared from
6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic
acid dihydrochloride and N-(2-aminoethyl)pyrrolidine in a manner
substantially analogous to Procedure B (See herein Example 8).
Observed mass 371 (M.sup.++1). ##STR24##
EXAMPLE 12
[0081]
[6-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-(-
4-phenyl-piperazin-1-yl)-methanone is prepared from
6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic
acid dihydrochloride and 1-phenyl-piperazine in a manner
substantially analogous to Procedure B (See herein Example 8).
Observed mass 419 (M.sup.++1). ##STR25##
EXAMPLE 13
Synthesis of
[6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-(2-pyrro-
lidin-1-ylmethyl-pyrrolidin-1-yl)-methanone
[0082] Procedure C: Charged 25 mL round bottomed flask with
6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic
acid dihydrochloride (0.250 g., 0.720 mmoles., 1.00 eq.), 10 mL
methylene chloride, (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine
(0.111 g., 0.720 mmoles., 1.0 eq.), 1-hydroxy-7-azabenzotrizole
(0.0980 g., 0.720 mmoles., 1.00 eq.), and N-ethylmorpholine (0.166
g., 1.44 mmoles., 2.00 eq.). Added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.145
g., 0.756 mmoles., 1.05 eq.). Stirred at room temperature
overnight. The next day, removed solvents via reduced pressure.
Partitioned reaction mixture between methylene chloride and
saturated sodium bicarbonate solution. Extracted two more times
with methylene chloride. Combined organic extracts and washed with
water three times and with brine one time. Removed solvents via
reduced pressure to obtain 0.124 g. Purified using Biotage FLASH 25
M.RTM. silica gel cartridge (55 g. of silica gel) and eluting with
5% (2N ammonia in methanol):methylene chloride. Obtained 96.2 mg.
(yield=32%) of desired product. Mass spectrum (APCI):
411(M.sup.++1). ##STR26##
EXAMPLE 14
[0083]
[6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-(-
2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from
6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic
acid dihydrochloride and
(R)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner
substantially analogous to Procedure C (See herein Example 13).
Observed mass 411(M.sup.++1). ##STR27##
EXAMPLE 15
Synthesis of
(S)-(2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(5,6,7,8-tetrahydro-naphtha-
len-2-yl)-methanone
[0084] Procedure D: Charged 8 mL glass vial with
5,6,7,8-tetrahydro-2-naphthoic acid (150 mg., 0.851 mmoles., 1.2
eq.), 6 mL of 5:1:1 chloroform:acetonitrile:t-butanol,
(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (109 mg., 0.709
mmoles., 1.0 eq.) and 1-hydroxybenzotriazole hydrate (143.8 mg.,
1.06 mmoles, 1.5 eq.). Added N-cyclohexylcarbodiimide
N'-methylpolystyrene HL (0.739 g., loading=1.92 mmoles/g., 2.0
eq.). Capped vial and rotated for two days. Added
Tris-(2-aminoethyl)amine polystyrene (0.817 g., loading=4.34
mmoles/g., 5.0 eq.) and rotated reaction vial for several hours.
Filtered off resin and concentrated under a stream of nitrogen.
Purified crude material using a Biotage FLASH 40+M.RTM. cartridge
(100 g. of silica gel) and a (2N ammonia in methanol):methylene
chloride solvent system. Collected 189.6 mg. (yield=85%). Mass
spectrum (APCI): 313 (M.sup.++1). ##STR28##
EXAMPLE 16
[0085]
(R)-(2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(5,6,7,8-tetrahydro--
naphthalen-2-yl)-methanone is prepared from
(R)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner
substantially analogous to Procedure D (See herein Example 15).
Observed mass 313(M.sup.++1). ##STR29##
EXAMPLE 17
[0086]
(S)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(5,6,7,8-tetrahydro--
naphthalen-2-yl)-methane
[0087] Procedure E: All operations performed under nitrogen.
Charged round bottomed flask with
(S)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(5,6,7,8-tetrahydro-naphtha-
len-2-yl)-methanone (100 mg., 0.348 mmoles, 1.0 eq.) and 2.0 mL
anhydrous tetrahydrofuran. Added 0.6 mL 1M lithium aluminum hydride
in tetrahydrofuran (0.576 mmoles, 1.8 eq.) and heated at reflux for
several hours. Allowed to stir at room temperature over the
weekend. Added 2.0 g. of sodium sulfate decahydrate (Aldrich) and
allowed to stir for several hours. Filtered the reaction mixture
through a Celite.RTM. pad and removed solvents under reduced
pressure. Obtained a crude yield of 0.1966 g. Purified crude with
Biotage FLASH 25+S.RTM. cartridge (20 g. of silica gel) and a step
wise (2N ammonia in methanol):methylene chloride solvent gradient.
Recovered 47.3 mg. (yield=49%). Mass spectrum (APCI): 299
(M.sup.++1) ##STR30##
EXAMPLE 18
[0088]
(R)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(5,6,7,8-tetrahydro--
naphthalen-2-yl)-methane is prepared from
(R)-(2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(5,6,7,8-tetrahydro-naphtha-
len-2-yl)-methanone in a manner substantially analogous to
Procedure E (See herein Example 17). Observed mass 299(M.sup.++1).
TABLE-US-00001 TABLE 1 Exam- ple Number Structure 1 ##STR31## 2
##STR32## 3 ##STR33## 4 ##STR34## 5 ##STR35## 6 ##STR36## 7
##STR37## 8 ##STR38## 9 ##STR39## 10 ##STR40## 11 ##STR41## 12
##STR42## 13 ##STR43## 14 ##STR44## 15 ##STR45## 16 ##STR46## 17
##STR47## 18 ##STR48##
[0089] The pharmaceutical salts of the invention are typically
formed by reacting a compound of Formula I or II or III with an
equimolar or excess amount of acid or base. The reactants are
generally combined in a mutual solvent such as diethylether,
tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the
like for acid addition salts, or water, an alcohol or a chlorinated
solvent such as dichloromethane for base addition salts. The salts
normally precipitate out of solution within about one hour to about
ten days and can be isolated by filtration or other conventional
methods.
[0090] Acids commonly employed to form pharmaceutical acid addition
salts are inorganic acids such as hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the
like, and organic acids such as p-toluenesulfonic, methanesulfonic
acid, ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid,
carbonic acid, succinic acid, citric acid, tartaric acid, benzoic
acid, acetic acid, and the like. Preferred pharmaceutical acid
addition salts are those formed with mineral acids such as
hydrochloric acid, hydrobromic acid, and sulfuric acid, and those
formed with organic acids such as maleic acid, tartaric acid, and
methanesulfonic acid.
[0091] Bases commonly employed to form pharmaceutical base addition
salts are inorganic bases, such as ammonium or alkali or alkaline
earth metal hydroxides, carbonates, bicarbonates, and the like.
Such bases useful in preparing the salts of this invention thus
include sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium carbonate, sodium carbonate, sodium bicarbonate,
potassium bicarbonate, calcium hydroxide, calcium carbonate, and
the like. The potassium and sodium salt forms are particularly
preferred.
[0092] It should be recognized that the particular counterion
forming a part of any salt of this invention is not of a critical
nature, so long as the salt as a whole is pharmacologically
acceptable and as long as the counterion does not contribute
undesired qualities to the salt as a whole.
[0093] The optimal time for performing the reactions of the Schemes
and the Route can be determined by monitoring the progress of the
reaction via conventional chromatographic techniques. Furthermore,
it is preferred to conduct the reactions of the invention under an
inert atmosphere, such as, for example, argon, or, particularly,
nitrogen. Choice of solvent is generally not critical so long as
the solvent employed is inert to the ongoing reaction and
sufficiently solubilizes the reactants to effect the desired
reaction. The compounds are preferably isolated and purified before
their use in subsequent reactions. Some compounds may crystallize
out of the reaction solution during their formation and then
collected by filtration, or the reaction solvent may be removed by
extraction, evaporation, or decantation. The intermediates and
final products of Formula I or II or III may be further purified,
if desired by common techniques such as recrystallization or
chromatography over solid supports such as silica gel or
alumina.
[0094] The skilled artisan will appreciate that not all
substituents are compatible with all reaction conditions. These
compounds may be protected or modified at a convenient point in the
synthesis by methods well known in the art.
[0095] The compound of Formula I or II or III is preferably
formulated in a unit dosage form prior to administration.
Therefore, yet another embodiment of the present invention is a
pharmaceutical composition comprising a compound of Formula I or II
or III and one or more pharmaceutically acceptable carriers,
diluents or excipients.
[0096] The present pharmaceutical compositions are prepared by
known procedures using well-known and readily available
ingredients. In making the formulations of the present invention,
the active ingredient (Formula I or II or III compound) will
usually be mixed with a carrier, or diluted by a carrier, or
enclosed within a carrier which may be in the form of a capsule,
sachet, paper or other container. When the carrier serves as a
diluent, it may be a solid, semisolid or liquid material that acts
as a vehicle, excipient, or medium for the active ingredient. Thus,
the compositions can be in the form of tablets, pills, powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions,
solutions, syrups, aerosol (as a solid or in a liquid medium), soft
and hard gelatin capsules, suppositories, sterile injectable
solutions and sterile packaged powders.
[0097] Some examples of suitable carriers, excipients, and diluents
include lactose, dextrose, sucrose, sorbitol, mannitol, starches,
gum acacia, calcium phosphate, alginates, tragacanth, gelatin,
calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water syrup, methyl cellulose, methyl and
propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
The formulations can additionally include lubricating agents,
wetting agents, emulsifying and suspending agents, preserving
agents, sweetening agents or flavoring agents. The compositions of
the invention may be formulated so as to provide quick, sustained
or delayed release of the active ingredient after administration to
the patient.
[0098] The compositions of the present invention may be formulated
in sustained release form to provide the rate controlled release of
any one or more of the components or active ingredients to optimize
the therapeutic effects, i.e., antihistaminic activity and the
like. Suitable dosage forms for sustained release include layered
tablets containing layers of varying disintegration rates or
controlled release polymeric matrices impregnated with the active
components and shaped in tablet form or capsules containing such
impregnated or encapsulated porous polymeric matrices.
[0099] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injections or addition of
sweeteners and opacifiers for oral solutions, suspensions and
emulsions. Liquid form preparations may also include solutions for
intranasal administration.
[0100] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier such as inert compressed
gas, e.g. nitrogen.
[0101] For preparing suppositories, a low melting wax such as a
mixture of fatty acid glycerides such as cocoa butter is first
melted, and the active ingredient is dispersed homogeneously
therein by stirring or similar mixing. The molten homogeneous
mixture is then poured into convenient sized molds, allowed to cool
and thereby solidify.
[0102] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration, Such liquid forms
include solutions, suspensions and emulsions.
[0103] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions may take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as a re
conventional in the art for this purpose.
[0104] Preferably the compound is administered orally.
[0105] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active components, e.g., an effective amount to achieve the desired
purpose.
[0106] The quantity of the inventive active composition in a unit
dose of preparation may be generally varied or adjusted from about
0.01 milligrams to about 1,000 milligrams, preferably from about
0.01 to about 950 milligrams, more preferably from about 0.01 to
about 500 milligrams, and typically from about 1 to about 250
milligrams, according to the particular application. The actual
dosage employed may be varied depending upon the patient's age,
sex, weight and severity of the condition being treated. Such
techniques are well known to those skilled in the art. Generally,
the human oral dosage form containing the active ingredients can be
administered 1 or 2 times per day.
Utility
[0107] Compounds of Formula I or II or III are effective as
histamine H3 receptor antagonists or inverse agonists. More
particularly, these compounds are selective histamine H3 receptor
antagonists that have little or no affinity for histamine receptor
GPRv53(H4R). As selective antagonists, the compounds of Formula I
or II or III are useful in the treatment of diseases, disorders, or
conditions responsive to the inactivation of the histamine H3
receptor, including but not limited to obesity and other
eating-related disorders. It is postulated that selective
antagonists of H3R will raise brain histamine levels and possibly
that of other monoamines resulting in inhibition of food
consumption while minimizing peripheral consequences. Although a
number of H3R antagonists are known in the art, none have proven to
be satisfactory obesity drugs. There is increasing evidence that
histamine plays an important role in energy homeostasis. Histamine,
acting as a neurotransmitter in the hypothalamus, suppressed
appetite. Histamine is an almost ubiquitous amine found in many
cell types and it binds to a family of G protein-coupled receptors
(GPCRs). This family provides a mechanism by which histamine can
elicit distinct cellular responses based on receptor distribution.
Both the H1R and H2R are widely distributed. H3R is primarily
expressed in the brain, notably in the thalamus and caudate
nucleus. High density of expression of H3R was found in feeding
center of the brain. A novel histamine receptor GPRv53 has been
recently identified. GPRv53 is found in high levels in peripheral
white blood cells; only low levels have been identified in the
brain by some investigators while others cannot detect it in the
brain. However, any drug discovery effort initiated around H3R must
consider GPRv53 as well as the other subtypes.
[0108] The inventive compounds can readily be evaluated by using a
competitive inhibition Scintillation Proximity Assay (SPA) based on
a H3R binding assay using [3H] .alpha. methylhistamine as ligand.
Stable cell lines, including but not limited to HEK can be
transfected with cDNA coding for H3R to prepare membranes used for
the binding assay. The technique is illustrated below (Preparation
of Histamine Receptor Subtype Membranes) for the histamine receptor
subtypes.
[0109] Membranes isolated as described in (Preparation of Histamine
Receptor Subtype Membranes) were used in a [35S]GTP.sub..chi.S
functional assay. Binding of [35S]GTP.sub..chi.S to membranes
indicates agonist activity. Compounds of the invention of Formula I
or II or III were tested for their ability to inhibit binding in
the presence of agonists. Alternately, the same transfected cell
lines were used for a cAMP assay wherein H3R agonists inhibited
forskolin-activated synthesis of cAMP. Compounds of Formula I or II
or III were tested for their ability to permit forskolin-stimulated
cAMP synthesis in the presence of agonist.
Preparation of Histamine Receptor Subtype Membranes
A. Preparation H1R Membranes
[0110] cDNA for the human histamine 1 receptor (HIR) was cloned
into a mammalian expression vector containing the CMV promoter
(pcDNA3.1(+), Invitogen) and transfected into HEK293 cells using
the FuGENE Tranfection Reagent (Roche Diagnostics Corporation).
Transfected cells were selected using G418 (500 .mu./ml). Colonies
that survived selection were grown and tested for histamine binding
to cells grown in 96-well dishes using a scintillation proximity
assay (SPA) based radioligand binding assay. Briefly, cells,
representing individual selected clones, were grown as confluent
monolayers in 96-well dishes (Costar Clear Bottom Plates, #3632) by
seeding wells with 25,000 cells and growing for 48 hours
(37.degree. C., 5% CO.sub.2). Growth media was removed and wells
were rinsed two times with PBS (minus Ca.sup.2+ or Mg.sup.2+). For
total binding, cells were assayed in a SPA reaction containing 50
mM Tris-HCL (assay buffer), pH 7.6, 1 mg wheat germ agglutinin SPA
beads (Amersham Pharmacia Biotech, #RPNQ0001), and 0.8 nM
.sup.3H-pyrilamine (Net-594, NEN) (total volume per well .about.200
.mu.l). Astemizole (10 .mu.M, Sigma #A6424) was added to
appropriate wells to determine non-specific binding. Plates were
covered with FasCal and incubated at room temperature for 120
minutes. Following incubation, plates were centrifuged at 1,000 rpm
(.about.800 g) for 10 minutes at room temperature. Plates were
counted in a Wallac Trilux 1450 Microbeta scintillation counter.
Several clones were selected as positive for binding, and a single
clone (H1R40) was used to prepare membranes for binding studies.
Cell pellets, representing .about.10 grams, were resuspended in 30
ml assay buffer, mixed by vortexing, and centrifuged (40,000 g at
4.degree. C.) for 10 minutes. The pellet resuspension, vortexing,
and centrifugation was repeated 2 more times. The final cell pellet
was resuspended in 30 ml and homogenized with a Polytron Tissue
Homogenizer. Protein determinations were done using the Coomassie
Plus Protein Assay Reagent (Pierce). Five micrograms of protein was
used per well in the SPA receptor-binding assay.
B. Preparation H2R Membranes
[0111] cDNA for the human histamine 2 receptor was cloned,
expressed and transfected into HEK 293 cells as described above.
Histamine binding to cells was assayed by SPA described above. For
total binding, cells were assayed in a SPA reaction containing 50
mM Tris-HCl (assay buffer), pH 7.6, 1 mg wheat germ agglutinin SPA
beads (Amersham Pharmacia Biotech, #RPNQ0001), and 6.2 nM
.sup.3H-tiotidine (Net-688, NEN) (total volume per well=200 .mu.l).
Cimetidine (10 .mu.M, Sigma #C4522) was added to appropriate wells
to determine non-specific binding.
[0112] Several clones were selected as positive for binding, and a
single clone (H2R10) was used to prepare membranes for binding
studies. Five micrograms of protein was used per well in the SPA
receptor-binding assay.
C. Preparation of H3R Membranes
[0113] cDNA for the human histamine 3 receptor was cloned and
expressed as described in (A. Preparation H1R membranes), above.
Transfected cells were selected using G418 (500 .mu./ml), grown,
and tested for histamine binding by the SPA described above. For
total binding, cells were assayed in a SPA reaction described above
containing 50 mM Tris-HCL (assay buffer), pH 7.6, 1 mg wheat germ
agglutinin SPA beads (Amersham Pharmacia Biotech, #RPNQ0001), and 1
nM (3H)-n-alpha-methylhistamine (NEN, NET1027) (total volume per
well=200 .mu.l). Thioperimide was added to determine non-specific
binding. Several clones were selected as positive for binding, and
a single clone (H3R8) was used to prepare membranes for binding
studies described above. Five micrograms of protein was used per
well in the SPA receptor-binding assay.
[0114] All compounds set forth in the examples exhibited affinity
for the H3 receptor greater than 1 uM. Preferred compounds of the
invention exhibited affinity for the H3 receptor greater than 200
nM. Most preferred compounds of the invention exhibit affinity for
the H3 receptor greater than 20 nM.
D. Preparation of GPRv53 Membranes
[0115] cDNA for the human GPRv53 receptor was cloned and expressed
as described in (A. Preparation H1R membranes), above. Transfected
cells were selected, tested for histamine binding, and selected.
HEK293 GPRv53 50 cells were grown to confluency in DMEM/F12 (Gibco)
supplemented with 5% FBS and 500 ug/ml G418 and washed with
Delbecco's PBS (Gibco) and harvested by scraping. Whole cells were
homogenized with a Polytron tissuemizer in binding buffer, 50 mM
Tris pH 7.5. Cell lysates, 50 ug, were incubated in 96 well dishes
with 3 nM (3H) Histamine and compounds in binding buffer for 2
hours at room temperature. Lysates were filtered through glass
fiber filters (Perkin Elmer) with a Tomtec cell harvester. Filters
were counted with melt-on scintillator sheets (Perkin Elmer) in a
Wallac Trilux 1450 Microbeta Scintillation counter for 5
minutes.
Pharmacological Results
cAMP ELISA
[0116] HEK293H3R8 cells prepared as described above were seeded at
a density of 50,000 cells/well and grown overnight in DMEM/F12
(Gibco) supplemented with 5% FBS and 500 ug/ml G418. The next day
tissue culture medium was removed and replaced with 50 .mu.l cell
culture medium containing 4 mM 3-isobutyl-1-methylxanthine (Sigma)
and incubated for 20 minutes at room temperature. Antagonist were
added in 50 .mu.l cell culture medium and incubated for 20 minutes
at room temperature. Agonist R (-).alpha. methylhistamine (RBI) at
a dose response from 1.times.10.sup.-10 to 1.times.10.sup.-5 M was
then added to the wells in 50 .mu.l cell culture medium and
incubated for 5 minutes at room temperature. Then 50 .mu.l of cell
culture medium containing 20 .mu.M Forskolin (Sigma) was added to
each well and incubated for 20 minutes at room temperature. Tissue
culture medium was removed and cells were lysed in 0.1M HCl and
cAMP was measured by ELISA (Assay Designs, Inc.).
[35S] GTP .gamma.[S] Binding Assay
[0117] Antagonist activity of selected compounds was tested for
inhibition of [35S] GTP .gamma.[S] binding to H3R membranes in the
presence of agonists. Assays were run at room temperature in 20 mM
HEPES, 100 mM NaCl, 5 mM MgCl.sub.2 and 10 uM GDP at pH 7.4 in a
final volume of 200 ul in 96-well Costar plates. Membranes isolated
from H3R8-expressing HEK293 cell line (20 ug/well) and GDP were
added to each well in a volume of 50 .mu.l assay buffer. Antagonist
was then added to the wells in a volume of 50 .mu.l assay buffer
and incubated for 15 minutes at room temperature. Agonist R(-)alpha
methylhistamine (RBI) at either a dose response from
1.times.10.sup.-10 to 1.times.10.sup.-5 M or fixed concentration of
100 nM were then added to the wells in a volume of 50 .mu.l assay
buffer and incubated for 5 minutes at room temperature. GTP
.gamma.[35S] was added to each well in a volume of 50 .mu.l assay
buffer at a final concentration of 200 .mu.M, followed by the
addition of 50 .mu.l of 20 mg/ml WGA coated SPA beads (Amersham).
Plates were counted in Wallac Trilux 1450 Microbeta scintillation
counter for 1 minute. Compounds that inhibited more than 50% of the
specific binding of radioactive ligand to the receptor were
serially diluted to determine a K[i](nM). The results are given
below for the indicated compound. TABLE-US-00002 TABLE 2 Example Ki
(nM) 3 1.5 6 7.8
[0118] To investigate the selectivity of the antagonists for the
histamine receptors, a competitive binding assay described above
was performed. The ability of example 15 (structure given above) to
selectively inhibit binding to H3R, H1R, H2 and H4R was determined.
Importantly, the identification of H3R-specific antagonists that do
not bind the newly identified H4R was demonstrated. Until the
present invention, most known H3R antagonists also bound H4R. As
demonstrated in Table 3, example 15 did not inhibit binding H4R
compared to H3R. TABLE-US-00003 TABLE 3 Ki (nM) Compound H3R H4R
H1R H2 Example 15 1.8 .gtoreq.20,000 .gtoreq.20,000
.gtoreq.17,809
[0119] From the above description, one skilled in the art can
ascertain the essential characteristics of the present invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions. Thus, other embodiments are also
within the claims.
* * * * *